Non-Standard Amino Acid Conjugates of Amphetamine and Processes for Making and Using the Same

ABSTRACT

Disclosed are amphetamine prodrug compositions comprising at least one non-standard amino acid conjugate of amphetamine, a salt thereof, a derivative thereof, or a combination thereof. Methods of making and using the same are also disclosed.

RELATED APPLICATIONS

This application is a continuation of PCT/US07/87028, Publication No.1008/073918, filed on Dec. 10, 2007, which claims priority to andbenefit from U.S. provisional patent application No. 60/869,375, filedon Dec. 11, 2006, which are incorporated hereby in their entireties.

FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

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MICROFICHE/COPYRIGHT REFERENCE

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BACKGROUND OF THE INVENTION

The present technology describes, in general, novelprodrugs/compositions of the stimulant amphetamine (i.e.,1-phenylpropan-2-amine) as well as non-standard amino acid conjugates ofamphetamine, salts thereof, other derivatives thereof, and combinationsthereof. Additionally, the presently described technology also relatesgenerally to the methods of making and using these newprodrugs/compositions.

The presently described technology in at least one aspect is focused ona slow/sustained controlled release composition of amphetamine, inprodrug form, that allows slow/sustained/controlled delivery of thestimulant into the blood system of a human or animal within a safetherapeutic window upon oral administration. At least somecompositions/formulation of the current technology can lessen therebound effect, cardiovascular stress, addiction/abuse potential and/orother common stimulant side effects associated with amphetamine andsimilar compounds. Such compositions may also increase the duration oftherapeutic efficacy, ease of application, patient compliance and/or anycombination of these characteristics when administered, in particular,orally.

Stimulants, including amphetamine and its derivatives, enhance theactivity of the sympathetic nervous system and/or central nervous system(CNS) and are prescribed for the treatment of a range of conditions anddisorders predominantly encompassing, for example, attention deficithyperactivity disorder (ADHD), attention deficit disorder (ADD),obesity, narcolepsy, appetite suppression, depression, anxiety andwakefulness.

Attention deficit hyperactivity disorder (ADHD) in children has beentreated with stimulants for many years. However, more recently, theincrease in number of prescriptions for ADHD therapy in adult populationhas, at times, outperformed the growth of the pediatric market. Althoughthere are various drugs currently in use for the treatment of ADHD, suchas methylphenidate (commercially available from, for example, NovartisInternational AG (located in Basel, Switzerland) under the trademarkRitalin®) and non-stimulant atomoxetine (commercially from Eli Lilly andCompany (located in Indianapolis, Ind.) as Strattera®), amphetamine hasbeen the forerunner in ADHD therapy. Moreover, during classroom trialsnon-stimulants have shown to be less effective in improving behavior andattention of ADHD afflicted children than amphetamine derivatives.

Initial drug therapy for ADHD was limited to fast acting immediaterelease formulations of stimulants (e.g., Dexedrine®, puredextroamphetamine sulfate, commercially available from Smith Kline andFrench located in the United Kingdom) which triggered an array ofpotentially undesirable side effects including, for example, fastwear-off of the therapeutic effect of the stimulant active ingredientcausing rebound symptoms, cardiovascular stress/disorders (e.g.,increased heart rate, hypertension, cardiomyopathy), other side effects(e.g., insomnia, euphoria, psychotic episodes), addiction and abuse.

Behavioral deterioration (rebound/“crashing”) is observed in asignificant portion of children with ADHD as the medication wears off,typically in the afternoon or early evening. Rebound symptoms include,for example, irritability, crankiness, hyperactivity worse than in theunmedicated state, sadness, crying and in rare cases psychotic episodes.The symptoms may subside quickly or last several hours. Some patientsmay experience rebound/crashing so severe that treatment must bediscontinued. Rebound/crashing effects can also give rise to addictivebehavior by enticing patients to administer additional doses ofstimulant with the intent to prevent anticipated rebound/crashingnegative outcomes and side effects.

Stimulants, such as methylphenidate and amphetamine, have shown toexhibit noradrenergic and dopaminergic effects that can lead tocardiovascular events comprising, for example, increased heart rate,hypertension, palpitations, tachycardia and in isolated casescardiomyopathy, stroke, myocardial infarction and sudden death.Consequently, currently available stimulants expose patients withpre-existing structural cardiac abnormalities or other severe cardiacindications to even greater health risks and are frequently not used orused with caution in this population. It is notable, however, that thecardiovascular effects of stimulants, for example on heart rate andblood pressure, is dependent on the administered dose. As a result, atreatment which maintains the lowest effective stimulant bloodconcentrations for a therapeutically beneficial duration is believed todemonstrate fewer cardiovascular risks.

Amphetamine and many of its derivatives (e.g., methamphetamine,3,4-methylenedioxy-methamphetamine/“Ecstacy”) are widely abused forvarious purposes such as euphoria, extended periods ofalertness/wakefulness, or rapid weight loss or by actual ADHD patientswho developed excessive self-dosing habits to prevent rebound symptomsfrom manifesting, for example, in anxiety or depression. The effectsdesired by potential abusers originated from the stimulation of thecentral nervous system and prompted a Schedule II or even Schedule Iclassification for amphetamine (d- and l-amphetamine individually andany combination of both are Schedule II) and certain derivatives thereofafter passage of the Controlled Substance Act (CSA) in 1970. Bothclassifications are defined by the high propensity for abuse. ScheduleII drugs have an accepted medical use while Schedule I substances do notpursuant to the CSA. So far, all amphetamine products, includingcompositions with sustained release formulations and prodrugs thereof,are obligated to include a black box warning on the drug label to informpatients about the potential for amphetamine abuse and dependence.

It has been shown in the conventional art that most side effects ofamphetamines are caused by a large initial spike in blood concentrationof the stimulant which quickly erodes to levels below therapeuticeffectiveness (typically within 4-6 hours). As a consequence, the highpotency of dextroamphetamine (d-amphetamine) was subsequently modulatedby a series of new drugs with increasingly sustained release profilesachieved by delivering amphetamine more slowly into the blood streamwith the goal to create safer and less abusable treatment outcomes andregimens. The methods and technologies for generating smaller spikes indrug blood concentrations include, for example, use of mixed salts andisomer compositions (i.e., different salts of d- and less potentl-amphetamine), extended/controlled/sustained release formulations(e.g., Adderall X® commercially available from Shire U.S., Inc. locatedin Wayne, Pa.) and, most recently, prodrugs of amphetamine (Vyvanse™also commercially available from Shire). The ideal drug treatment optionshould produce stimulant blood concentrations within a narrowtherapeutic window for an extended time duration followed by a prolongedfade-out period in order to minimize cardiovascular stress andbehavioral deterioration, and would also exhibit anti-abuse properties.

Besides immediate release formulations, newer sustained releaseformulations have been developed with the objective to provide atherapeutic treatment option that offers the convenience of a singledaily dosing regimen versus multiple quotidian administrations. Suchformulations also have the objective of imparting or rendering aeuphoric response. Sustained release formulations commonly consist ofdrug particles coated with a polymer or polymer blend that delays andextends the absorption of the active drug substance by thegastrointestinal tract for a relatively defined period of time. Suchformulations frequently embed the therapeutic agent/activeingredient/drug within a hydrophilic hydrocolloid gelling polymer matrix(e.g., hydroxypropyl methylcellulose, hydroxypropyl cellulose orpullulan). This dosage formulation in turn becomes a gel upon enteringan acidic medium, as found in the stomach of humans and animals,thereupon slowly effusing the therapeutic agent/active ingredient/drug.However, the dosage formulation dissolves in an alkaline medium, asfound in the intestines of humans and animals, concurrently liberatingthe drug more quickly in an uncontrolled manner. Some formulations, suchas acrylic resins, acrylic latex dispersions, cellulose acetatephthalate, and hydroxypropyl methylcellulose phthalate, offer improvedsustained release in the intestines by being resistant to acidicenvironments and dispensing the active ingredient only at elevated pHvia a diffusion-erosion mechanism, either by themselves or mixed withhydrophilic polymers.

Sustained release formulations have been moderately effective inproviding an improved and extended dosage form over immediate releasetablets. Nonetheless, such formulations are potentially subject toinconsistent, erratic or premature release of the therapeutic agent dueto failure of the polymer material and they also usually allow easyextraction of the active ingredient utilizing a simple physicalprocedure. Since single daily dose formulations contain a greater amountof amphetamine than immediate release formulations, they are moreattractive to potential abusers, consequently making the extractabilityof drug substance an additional undesirable property. It is also, atleast in part, a reason for increased drug diversion, especially evidentby selling or trading of medication by school children who are ADHDpatients and in possession of sustained release amphetamine capsules.The obtained stimulants are then abused by classmates without thedisorder by either ingesting high doses or snorting the drug materialafter crushing it.

U.S. Pat. No. 7,105,486 (to assignee New River Pharmaceuticals,hereinafter the “'486 patent”) appears to describe compounds comprisinga chemical moiety (namely L-lysine) covalently attached to amphetamine,compositions thereof, and methods of using the same. Allegedly, thesecompounds and their compositions are useful for reducing or preventingabuse and overdose of amphetamine. The '486 patent also describes thatusing any amino acid other than l-lysine (Table 46) will not give riseto the same in vivo properties demonstrated by l-lysine-d-amphetamine(Lys-Amp, Vyvanse™). Additionally, since lysine is a natural andstandard amino acid, the breakdown of the new prodrug occurs faster thandesired to reduce the side effect profile. Thus, quick release ofamphetamine from such standard amino acid conjugate compositions maycause an increase in blood pressure and heart rate found in otherconventional stimulant treatments. As a result, there still exists aneed within the art for a safer dosage form of amphetamine, andtreatment regimen that is therapeutically effective and can providesustained release and sustained therapeutic effect

BRIEF SUMMARY OF THE INVENTION

The presently described technology provides, in part, compositionscomprising at least one amphetamine conjugated with a non-standard aminoacid, or a salt thereof, which can diminish or eliminate pharmacologicalactivity of the amphetamine until released in vivo. The non-standardamino acid conjugate(s) of the present technology is amphetamine in aprodrug form, and can be converted into its active form in the body bynormal metabolic processes. Although not wanting to be bound by anyparticular theory, one or more non-standard amino acid conjugates of thepresent technology are believed to be safer than other sustained releaseforms of amphetamine by providing controlled blood levels for aprolonged period of time, thus preventing the rebound effect,cardiovascular stress and euphoria associated with conventionalstimulant treatment options.

The presently described technology further provides methods ofcontrolled therapeutic delivery of amphetamine compositions by oraladministration. Release of amphetamine following oral administration ofthe non-standard amino acid conjugates of the present technology canoccur gradually over an extended period of time thereby eliminatingunintended elevations (e.g., blood level concentration spikes) of druglevels in the bloodstream of a human or animal patient. Again notwanting to be bound by any particular theory, it is also believed thatsuch spikes in blood levels can lead to a euphoric drug “high” andcardiovascular effects like increased blood pressure and heart rate.Additionally, sustained blood levels are achieved within an effectivetherapeutic range for a longer duration than other conventionaltherapies, thereby preventing a rebound effect.

At least some compositions comprising the amphetamine prodrugs of thepresent technology are resistant to abuse by parenteral routes ofadministration, such as intravenous “shooting,” intranasal “snorting,”or inhalation “smoking,” that are often employed during illicit use. Thepresent technology thus provides a stimulant based treatment modalityand dosage form for certain disorders requiring the stimulation of theCNS such as ADHD, ADD, obesity, narcolepsy, appetite suppressant,depression, anxiety, and wakefulness with reduced or prevented abusepotential. Although not wanting to be bound by any particular theory, itis believed that the treatment of such CNS conditions as noted abovewith compositions of the present technology results in substantiallydecreased abuse liability as compared to existing stimulant treatmentmodalities and dosage forms.

At least some compositions comprising the amphetamine prodrugs of thepresent technology can also be used for treating stimulant (cocaine,methamphetamine) abuse and addiction, for improving battle fieldalertness, and/or for combating fatigue.

In a first aspect, the presently described technology provides acomposition comprising at least one non-standard amino acid conjugate ofamphetamine, a salt thereof, a derivative thereof, or a combinationthereof. Preferably, the non-standard amino acid is covalently attachedto amphetamine through the C-terminus of the non-standard amino acid.The N-terminus or the side chain amino group of the non-standard aminoacid may be in a free and unprotected state, or in the form of a saltthereof. The non-standard amino acid moiety can be derived from anon-standard amino acid that is either a dextro-(d-) or levo-(l-) formamino acid, racemic amino acid, or a mixture thereof.

In accordance with some embodiments, non-standard amino acids are used.Examples of preferred non-standard amino acids to be conjugated with theamphetamine include, but are not limited to, ornithine, homoarginine,selenomethionine, citrulline, sarcosine, homoserine, and homocitrulline.More preferred non-standard amino acids for at least some embodiments ofthe present technology are homoarginine and ornithine. Homoarginine ismost preferred for at least some embodiments of the present technology.

The compositions of the present technology preferably have no or asubstantially decreased pharmacological activity when administeredthrough injection or intranasal routes of administration. However, theyremain orally bioavailable. The bioavailability can be a result of thehydrolysis of the covalent linkage following oral administration.Hydrolysis is time-dependent, thereby allowing amphetamine and othermetabolites such as p-hydroxyamphetamine and p-hydroxyephedrine tobecome available in its active form over an extended period of time. Inat least one further embodiment, release of amphetamine is diminished oreliminated when the composition of the present technology is deliveredby parenteral routes.

For example, in one embodiment, the composition of the presenttechnology maintains its effectiveness and abuse resistance followingthe crushing of the tablet, capsule or other oral dosage form utilizedto deliver the therapeutic component (i.e., active ingredient/drug) dueto the inherent controlled release components being a property of thecomposition not formulation. In contrast, conventional extended releaseformulations used to control the release of amphetamine are subject torelease of up to the entire amphetamine content immediately followingcrushing. When the content of the crushed tablet is injected or snorted,the large dose of amphetamine produces the “rush” effect sought byaddicts.

In another aspect, the presently described technology provides a methodfor treating a human or animal patient with a disorder or conditionrequiring the stimulation of the patient's CNS (Central Nervous System),comprising the step of orally administering to the patient in need acomposition formulated for oral dosage comprising at least onenon-standard amino acid conjugate of amphetamine of the presenttechnology, wherein the blood levels of amphetamine in the patient'sbody can maintain a therapeutically effect level throughout a given day,and do not lead to behavioral deterioration or the rebound effect.

In another aspect, the presently described technology provides a methodfor treating a human or animal patient with a disorder or conditionrequiring the stimulation of the patient's CNS (Central Nervous System),comprising the step of orally administering to the patient in need acomposition formulated for oral dosage comprising at least onenon-standard amino acid conjugate of amphetamine of the presenttechnology, wherein the blood levels of amphetamine in the patient'sbody are not unnecessarily elevated (i.e., blood level spikes) thuspreventing additional cardiovascular stress through, for example,increased blood pressure and/or heart rate.

In another aspect, the presently described technology provides a methodfor treating a human or animal patient with a disorder or conditionrequiring the stimulation of the patient's CNS, comprising orallyadministering to the patient in need a composition formulated for oraldosage comprising at least one non-standard amino acid conjugate ofamphetamine, wherein the blood levels of amphetamine in the patient'sbody can maintain a therapeutically effect level, but do not result inan euphoric effect (such as that observed with abuse of amphetamines).

In a further aspect, the presently described technology provides amethod for delivering amphetamine, comprising providing a human oranimal patient with a therapeutically effective amount of at least onenon-standard amino acid conjugate of amphetamine, which can provide atherapeutically bioequivalent area under the curve (AUC) when comparedto free amphetamine, but does not provide a concentration max (C_(max))which results in an increased heart rate, increased blood pressure ordrug related euphoria when taken orally.

Other objects, advantages and embodiments of the invention are describedbelow and will be obvious from this description and practice of theinvention.

BRIEF DESCRIPTION OF SEVERAL VIEWS OF THE DRAWINGS

FIG. 1 shows the mean plasma concentration curves (n=5) of d-amphetaminereleased by l-homoarginine-d-amphetamine or l-lysine-d-amphetamine inthe biological oral study of Example 7.

FIG. 2 shows the relative blood levels of d-amphetamine released fromboth Lys-Amp and hArg-Amp in the study described in FIG. 1 and Table 2.

FIGS. 3 and 4 show the difference in blood levels obtained from thestudy described in FIG. 2.

FIG. 5 shows the average pharmacokinetic (PK) results of the other oralstudies in Example 7 for four (4) oral studies (n=20 per vehicle) of1-homoarginine-d-amphetamine and 1-lysine-d-amphetamine.

FIG. 6 shows the mean plasma concentration curves (n=5) of d-amphetaminereleased by hArg-Amp or Orn-Amp in the oral pharmacokinetic study ofExample 8.

FIG. 7 shows the mean plasma concentration curves (n=5) of d-amphetaminereleased by hArg-Amp, Orn-Amp and Cit-Amp in the oral pharmacokineticstudy of Example 9.

FIG. 8 shows the mean plasma concentration curves (n=5) of d-amphetaminereleased by hArg-Amp or Orn-Amp in the intranasal study of Example 10.

FIG. 9 shows the mean plasma concentration curves (n=5) of d-amphetaminereleased by hArg-Amp or Orn-Amp in the intranasal study of Example 11.

DETAILED DESCRIPTION OF THE INVENTION

The presently described technology relates to novelprodrugs/compositions of amphetamine, more specifically to non-standardamino acid conjugates of amphetamine, salts thereof, derivativesthereof, or combinations thereof. Methods of making and using theprodrugs/compositions of the present technology are also disclosed.

As used herein, a “non-standard” amino acid refers to an amino acid thatis not one of the “standard” 20 amino acids and they may be derived fromeither natural or synthetic sources. “Non-standard” amino acids arenon-essential, and are not readily incorporated into proteins of naturalorigin. They are either metabolites or precursors in various metabolicpathways. With the exception of selenocysteine, there is no humangenetic codon for the formation of non-standard amino acids. Forexample, the diamino acid lysine is a standard, essential amino acid,and is therefore excluded from the scope of the presently describedtechnology.

As used herein, “amphetamine” shall mean any of the sympathomimeticphenethylamine derivatives which have central nervous system stimulantactivity, including, but not limited to, amphetamine(alpha-methyl-phenethylamine), methamphetamine, p-methoxyamphetamine,methylenedioxyamphetamine, 2,5-dimethoxy-4-methylamphetamine,2,4,5-trimethoxyamphetamine, 3,4-methylenedioxy-methamphetamine, andmethylphenidate.

As used herein, “in a manner inconsistent with the manufacturer'sinstructions” or similar expression is meant to include, but is notlimited to, consuming amounts greater than amounts described on thelabel or ordered by a licensed physician, and/or altering by any means(e.g., crushing, breaking, melting, separating, etc.) the dosageformulation such that the composition may be injected, inhaled orsmoked.

As used herein, the phrases such as “decreased,” “reduced,” “diminished”or “lowered” is meant to include at least a 10% change inpharmacological activity with greater percentage changes being preferredfor reduction in abuse potential and overdose potential. For instance,the change may also be greater than 25%, 35%, 45%, 55%, 65%, 75%, 85%,95%, 96%, 97%, 98%, 99%, or increments therein.

In accordance with some embodiments, the present technology providesamphetamine in a prodrug form. More specifically, the amphetamineprodrug comprises at least one non-standard amino acid covalently bondedor attached to amphetamine, which includes different forms or modifiedforms of sympathomimetic phenethylamine derivatives. According to thepresently described technology, any non-standard amino acid can be usedto produce the amino acid conjugate of amphetamine. The amino acid canbe either the dextro-(d-) or levo-(l-) form of the amino acid, a racemicmixture of the amino acid, or a mixture thereof.

In some embodiments, non-standard amino acids are used to produce theamino acid conjugates of amphetamine. One group of preferrednon-standard amino acids suitable for the presently described technologycan be represented by the following general formula:

NH₂—CH(R)—COOH

wherein R is a side chain of one of the non-standard amino acids. Insome preferred embodiments, R comprises the side chain of ornithine(—CH₂CH₂CH₂NH₂) or homoarginine (—CH₂CH₂CH₂CH₂NH—(C═NH)—NH₂). In somealternative embodiments, R can comprise the side chain of any othernon-standard amino acid.

In accordance with the presently described technology, the non-standardamino acid is attached to amphetamine to make the non-standard aminoacid conjugate of amphetamine or salts thereof. Preferably, thenon-standard amino acid is covalently attached to amphetamine throughthe C-terminus of the amino acid. The N-terminus or, when it is present,the side chain amino group of the amino acid may be in a free andunprotected state, or in the form of a salt thereof. Alternatively, insome embodiments, the non-standard amino acid can be attached toamphetamine through the N-terminus. Examples of salts of non-standardamino acid conjugates of amphetamine that can be formed and administeredto patients in accordance with the presently described technologyinclude, but are not limited to, mesylate, hydrochloride, sulfate,oxalate, triflate, citrate, malate, tartrate, phosphate, nitrate, andbenzoate salts, and mixtures thereof.

Some of the preferred non-standard amino acid conjugates of amphetamineof the present technology can be represented by the following generalformula,

wherein R=the side chain of any non-standard amino acid. Morepreferably, R is homoarginine or ornithine due to their low toxicityprofile in humans and animals.

Examples of non-standard amino acids that are contemplated for thepresently described technology include, but are not limited to:ornithine, homoarginine, pyrrolysine, lanthionine, 2-aminoisobutyricacid, dehydroalanine, B-alanine, homocysteine, homoserine,2-oxoarginine, gamma-aminobutyric acid (GABA), 4-amino butanoic acid,all phosphorylated standard amino acids, all hydroxylated standard aminoacids, all acetylated standard amino acids, all succinated standardamino acids, all methylated standard amino acids, LL-2,6-diaminopimelicacid, 6-aminohexanoic acid, L-2-aminoadipate 6-semialdehyde, pipecolicacid, D-threo-2,4-diaminopentanoate, 2-amino-4-oxopentanoic acid,L-erythro-3,5-diaminohexanoic acid, (S)-5-amino-3-oxohexanoic acid,N6-hydroxy-L-lysine, N6-acyl-L-lysine, L-saccharopine, 5-aminovalericacid, N6-methyl-L-lysine, N6,N6-dimethyl-L-lysine,N6,N6,N6-trimethyl-L-lysine, 3-hydroxy-N6,N6,N6-trimethyl-L-lysine,4-trimethylammoniobutanoic acid, 5-hydroxy-L-lysine, L-citrulline,2-oxo-4-hydroxy-5-aminovalerate, pyrrole-2-carboxylate,L-erythro-4-hydroxyglutamic acid, trans-4-hydroxy-L-proline,4-oxoproline, N-methylglycine (sarcosine), 3-sulfino-L-alanine,O3-acetyl-L-serine, selenomethionine, selenocysteine,Se-methylselenomethionine, Se-methylselenocysteine, selenocystathionine,selenocysteine selenate, and cystathione.

Some structural examples of non-standard amino acids are shown below:

Preferred non-standard amino acids for the present technology include,but are not limited to, ornithine, homoarginine, selenomethionine,citrulline, sarcosine, homoserine, and homocitrulline. For at least someembodiments, homoarginine and ornithine are more preferred. Homoarginineis most preferred for at least some embodiments of the presenttechnology.

The amphetamine can be in d-form, l-form, or racemic form, or can be amixture thereof. For example, when l-ornithine (l-2,5-diaminopentanoicacid) is used, it can be chemically conjugated to a d- or l-amphetamineto produce a novel prodrug of amphetamine (e.g.,2,5-diamino-N(1-phenylpropan-2-yl)pentanamide).

To conjugate a non-standard amino acid with amphetamine, the one or moreamino groups are preferably protected before the amino acid is reactedwith amphetamine. The non-standard amino acid whose amino group(s) areprotected can be referred to as an N-protected amino acid. Agents andmethods for protecting amino groups in a reactant are known in the art.One can either protect the amino groups prior to reaction, or usecommercially available N-protected amino acids directly. Preferably, thecarboxylic acid group in the N-protected amino acid is activated by anacid activating agent to help the reaction of the N-protected amino acidwith amphetamine. General information about the reaction of amino acidsto form peptide bonds can be found in, for example, G. C. Barett, D. T.Elmare, Amino Acids and Peptides, page 151-156, Cambridge UniversityPress, UK (1st edition, 1998); Jones, J., Amino Acid and PeptideSynthesis, pages 25-41, Oxford University Press, UK (2nd edition, 2002),which are incorporated herein by reference in their entirety.

One category of acid activating agent well known in the art iscarbodiimides. Examples of carbodiimide acid activating agents include,but are not limited to, dicyclohexylcarbodiimide (DCC),1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide (EDCI), anddiisopropylcarbodiimide (DIPCDI). The N-protected amino acid conjugateof amphetamine resulting from the reaction of the N-protected amino acidand amphetamine can then be de- or un-protected with a strong acid toproduce the corresponding final salt form of the non-standard amino acidconjugate of amphetamine. Scheme 1 below shows a general syntheticscheme when ornithine is used as the non-standard amino acid.

In accordance with some embodiments of the presently describedtechnology, d-amphetamine (dextroamphetamine) is preferably used andl-ornithine is a preferred non-standard amino acid. In accordance withsome other embodiments, the prodrug of d-amphetamine can be used incombination with a prodrug of l-amphetamine or l-amphetamine itself.

In accordance with some other preferred embodiments, synthesis ofOrn-Amp (l-ornithine-d-amphetamine) can be accomplished in two steps asshown in reaction Scheme 2 below. The first step is the coupling ofBoc-Orn(Boc)-OH with d-amphetamine using EDCI. N-hydroxysuccinimide(NHS) can be added to form an in-situ activated ester withdiisopropylethylamine (DIPEA) used as a co-base. The product can then besubjected to deprotection with methanesulfonic acid which also forms thecorresponding dimesylate salt.

Besides ethyl acetate, examples of other solvents that can be used inthe presently described technology include, but are not limited to,isopropyl acetate (IPAC), acetone, and dichloromethane (DCM). A mixtureof different solvents can also be used. When a polar solvent isrequired, water, dimethylformamide (DMF), 1,4-dioxane ordimethylsulfoxide (DMSO) can be used. Co-bases such as tertiary aminesmay or may not be added in the coupling reaction. Examples of suitableco-bases include 1-methylmorpholine (NMM), triethylamine (TEA), etc.

It is important to note that preparation of Orn-Amp requires additionalexperimentation compared to the prior art. It has been surprisinglyfound that significant changes of the solubility in starting material ofBoc-Orn(Boc)-OH required the use of DMF instead of less polar solventsstated previously. In addition, due to the unique solubility differencesof Orn-Amp 2MsOH as compared to either Lys-Amp 2HCl or Lys-Amp 2MsOH,the procedures of the conventional art would not give rise to Orn-Amp2MsOH without significant experimentation. Also, formation of the freebase of amphetamine was performed in situ and was not isolated. Theformation of the activated ester was performed in situ with the additionreaction following in the same reaction vessel. Quite surprisingly,these changes to solubility and reaction conditions are not readilyapparent from previously published procedures or from the overallstructures themselves and were unpredictable and unexpected which leadto the discovery of the presently described technology.

In accordance with some other preferred embodiments, synthesis ofl-homoarginine-d-amphetamine dihydrochloride (hArg-Amp) can beaccomplished in three steps as shown in Scheme 3 below. In the firststep, an N-protected hArg (e.g., Boc-hArg(NO₂)) is coupled withd-amphetamine using EDCI. NHS is added to form an in-situ activatedester with DIPEA used as a co-base. The product is then subjected tohydrogenation under acidic conditions followed by deprotection withhydrochloric acid which forms the corresponding dihydrochloride salt.

The preparation of hArg-Amp required extensive modifications topreviously published methods and syntheses. First, Boc-hArg(NO₂)—OHrequired use of DMF to solubilize the material prior to reaction.Second, formation of the free base of amphetamine was performed in situand was not isolated. Also, the formation of the activated ester wasperformed in situ with the addition reaction following in the samereaction vessel. Homoarginine is different from other standard andnon-standard amino acids in that it requires a separate step ofdeprotection to remove the nitro group from the side chain. Failure todo so correctly can lead to undesirable products that do not perform invivo with respect to the desired therapeutic outcomes discussed herein.

In some other preferred embodiments of the present technology,1-citrulline-d-amphetamine hydrochloride (Cit-Amp) can be synthesized asshown in reaction Scheme 4 below in three overall steps. The first stepinvolves the activation of Boc-Cit-OH to form an activated ester usingDCC and NHS followed by the addition of d-amphetamine to produce theprotected Boc-Cit-Amp. Deprotection using 4N HCl in dioxane gives thecorresponding hydrochloride salt.

At least some compounds of the present technology have no or asubstantially decreased pharmacological activity when delivered throughalternative routes of administration like intranasal or intravenous.However, they remain orally bioavailable at a level similar or slightlylower than other controlled release forms. The bioavailability can be aresult of the hydrolysis of the covalent linkage following oraladministration. Hydrolysis is time-dependent, thereby allowingamphetamine to become available in its active form over an extendedperiod of time in a very controlled fashion. Therefore, the compounds ofthe present technology can release amphetamine over an extended periodand provide a therapeutically bioequivalent area under the curve (AUC)when compared to other controlled release forms of amphetamine (AdderallX® or Vyvanse™), with little or no spike in concentration max (C_(max))or equivalent C_(max). Not wanting to be bound by any particular theory,it is believed that since non-standard amino acids are used to producethe prodrug, the in vivo breakdown of the prodrug by enzymes would occurat a slower rate than, for example, when a standard amino acid is usedto conjugate amphetamine. This will allow the prodrug to releaseamphetamine slowly and, preferably, only under in vivo conditions.

As a person of ordinary skill in the art will understand, drug productsare considered pharmaceutical equivalents if they contain the sameactive ingredient(s), are of the same dosage form, route ofadministration and are identical in strength or concentration.Pharmaceutically equivalent drug products are formulated to contain thesame amount of active ingredient in the same dosage form and to meet thesame or compendial or other applicable standards (i.e., strength,quality, purity, and identity), but they may differ in characteristicssuch as shape, scoring configuration, release mechanisms, packaging,excipients (including colors, flavors, preservatives), expiration time,and, with certain limits, labeling. Drug products are considered to betherapeutic equivalents only if they are pharmaceutical equivalents andif they can be expected to have the same clinical effect and safetyprofile when administered to patients under the conditions specified inthe labeling. The term “bioequivalent,” on the other hand, describespharmaceutical equivalent or pharmaceutical alternative products thatdisplay comparable bioavailability when studied under similarexperimental conditions.

Standard amino acids such as lysine are not contemplated for thepresently described technology, because lysine is an essential part ofall dietary requirements, it would be expected that the prodrugconjugated with lysine would be released at a faster rate. By usingnon-standard amino acids, the release rate of amphetamine will bereduced due to the difference in overall digestion rate of non-standardamino acid conjugates of amphetamine versus standard amino acidconjugates of amphetamine such as lysine-amphetamine conjugate. Thisreduction in the rate of hydrolysis will decrease the incidence ofcardiac side effects including higher blood pressure, rapid heart rate,and/or other subsequent side effects associated with conventionalamphetamine treatment.

In accordance with the presently described technology, release ofamphetamine after oral administration of the prodrug of the presentlydescribed technology would occur under desired physiological conditions.Preferably, other routes of administration (e.g., intranasal orintravenous) do not break the prodrug down to any appreciable extent.Also preferably, external means (chemical, enzymatic or other) will notbreak the prodrug down to any appreciable extent either. The breakdownratio of the prodrug that can be achieved through external means ispreferably less than about 50%, alternatively less than about 25%,alternatively less than about 20%, alternatively less than about 10%.

The presently described technology utilizes covalent modification ofamphetamine by a non-standard amino acid to decrease its potential forcausing behavioral deterioration or the rebound effect. It is believedthat since the amphetamine is covalently modified to form thenon-standard amino acid conjugate of the present technology and releasesslowly over the entire length of the day, little or no rebound effectcan occur due to the slow continuous release of the activeingredient/drug/therapeutic component.

Compounds, compositions and methods of the presently describedtechnology are also believed to provide reduced potential for rebound,reduced potential for abuse or addiction, and/or improve amphetamine'sstimulant related toxicities. By limiting the blood level spike, dosesare kept at levels required for a clinically significant effect withoutthe unnecessary levels administered with other therapies. It is widelyheld that these spikes in blood levels can lead to cardiovasculartoxicity in the form of higher blood pressure and rapid heart rate inaddition to the euphoria encountered in drug abuse. Also, with a fullday therapy, the risk of re-dosing is lowered, thus preventingadditional toxicities or drug abuse issues.

The amphetamine prodrugs of the presently described technology could beused for any condition requiring the stimulation of the central nervoussystem (CNS). These conditions include, for example, attention deficithyperactivity disorder (ADHD), attention deficit disorder (ADD),obesity, narcolepsy, appetite suppressant, depression, anxiety, andwakefulness. Amphetamine stimulants have also demonstrated usefulness intreating stimulant (e.g., cocaine, methamphetamine) abuse and addiction.Amphetamine stimulants have also been used extensively to improve battlefield alertness and to combat fatigue.

Therefore, in accordance with some embodiments, the presently describedtechnology provides amphetamine compositions comprising at least oneamphetamine prodrug of the present technology.

One embodiment is a composition that can prevent behavioraldeterioration of amphetamine dosing comprising at least one non-standardamino acid conjugate of amphetamine.

Another embodiment is a composition for safely delivering amphetamine,comprising a therapeutically effective amount of at least onenon-standard amino acid conjugate of amphetamine wherein thenon-standard amino acid moiety can reduce the rate of absorption of theamphetamine as compared to delivering the unconjugated amphetamine oramphetamine conjugated to a standard amino acid.

Another embodiment of the present technology is a composition that canreduce amphetamine toxicity, comprising at least one non-standard aminoacid conjugate of amphetamine wherein the non-standard amino acid moietycan release amphetamine over the entire course of a day providing alimited behavioral deterioration effect.

Another embodiment of the present technology is a composition that canreduce amphetamine toxicity, comprising at least one non-standard aminoacid conjugate of amphetamine wherein the non-standard amino acid moietycan provide a serum release curve which does not increase aboveamphetamine's therapeutic level and does not cause blood level spiking.

Another embodiment of the present technology is a composition that canreduce bioavailability of amphetamine or prevent a toxic release profilein a patient, comprising at least one non-standard amino acid conjugateof amphetamine wherein the non-standard amino acid conjugate ofamphetamine can maintain a steady-state serum release curve which canprovide a therapeutically effective bioavailability but prevent spikingor increased blood serum concentrations compared to unconjugatedamphetamine or amphetamine conjugated with a standard amino acid.

Another embodiment of the present technology is a composition comprisingat least one non-standard amino acid conjugate of amphetamine that canprevent a C_(max) or equivalent C_(max) spike for amphetamine.

Another embodiment of the present technology is a composition comprisingat least one non-standard amino acid conjugate of amphetamine that canprevent a C_(max) or equivalent C_(max) spike for amphetamine when takenby means other than orally while still providing a therapeuticallyeffective bioavailability curve if taken orally.

In one or more embodiments, the non-standard amino acid conjugates ofamphetamine of the present technology may further comprise a polymerblend which comprises a hydrophilic polymer and/or a water-insolublepolymer. The polymers may be used according to industry standards tofurther enhance the sustained release/abuse resistant properties of theamphetamine prodrug of the present technology without reducing the abuseresistance. For instance, a composition might include: about 70% toabout 100% amphetamine prodrug of the present technology by weight, fromabout 0.01% to about 10% of a hydrophilic polymer (e.g. hydroxypropylmethylcellulose), from about 0.01% to about 2.5% of a water-insolublepolymer (e.g. acrylic resin), from about 0.01% to about 1.5% ofadditives (e.g. magnesium stearate), and from about 0.01% to about 1%colorant by weight.

Hydrophilic polymers suitable for use in the sustained releaseformulations include one or more natural or partially or totallysynthetic hydrophilic gums such as acacia, gum tragacanth, locust beangum, guar gum, or karaya gum, modified cellulosic substances such asmethylcellulose, hydroxymethylcellulose, hydroxypropyl methylcellulose,hydroxypropyl cellulose, hydroxyethylcellulose, carboxymethylcellulose;proteinaceous substances such as agar, pectin, carrageen, and alginates;and other hydrophilic polymers such as carboxypolymethylene, gelatin,casein, zein, bentonite, magnesium aluminum silicate, polysaccharides,modified starch derivatives, and other hydrophilic polymers known tothose of skill in the art, or a combination of such polymers. Thesehydrophilic polymers gel and would dissolve slowly in aqueous acidicmedia thereby allowing the amphetamine conjugate to diffuse from the gelin the stomach. When the gel reaches the intestines it would dissolve incontrolled quantities in the higher pH medium to allow further sustainedrelease. Preferred hydrophilic polymers are the hydroxypropylmethylcelluloses such as those manufactured by The Dow Chemical Companyand known as Methocel ethers, such as Methocel E1OM.

Other formulations according to one or more embodiments of the presenttechnology may further comprise pharmaceutical additives including, butnot limited to, lubricants such as magnesium stearate, calcium stearate,zinc stearate, powdered stearic acid, hydrogenated vegetable oils, talc,polyethylene glycol, and mineral oil; colorants such as Emerald GreenLake, FD&C Red No. 40, FD&C Yellow No. 6, D&C Yellow No. 10, or FD&CBlue No. 1 and other various certified color additives (See 21 CFR, Part74); binders such as sucrose, lactose, gelatin, starch paste, acacia,tragacanth, povidone polyethylene glycol, Pullulan and corn syrup;glidants such as colloidal silicon dioxide and talc; surface activeagents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate,triethanolamine, polyoxyethylene sorbitan, poloxalkol, and quaternaryammonium salts; preservatives and stabilizers; excipients such aslactose, mannitol, glucose, fructose, xylose, galactose, sucrose,maltose, xylitol, sorbitol, chloride, sulfate and phosphate salts ofpotassium, sodium, and magnesium; and/or any other pharmaceuticaladditives known to those of skill in the art. In one preferredembodiment, a sustained release formulation of the present technologyfurther comprises magnesium stearate and Emerald Green Lake.

The amphetamine compositions of the present technology, which comprisesat least one amphetamine prodrug of the present technology and can befurther formulated with excipients, may be manufactured according to anyappropriate method known to those of skill in the art of pharmaceuticalmanufacture. For instance, the amphetamine prodrug and a hydrophilicpolymer may be mixed in a mixer with an aliquot of water to form a wetgranulation. The granulation may be dried to obtain hydrophilic polymerencapsulated granules of the amphetamine prodrug. The resultinggranulation may be milled, screened, then blended with variouspharmaceutical additives such as, water insoluble polymers, and/oradditional hydrophilic polymers. The formulation may then be tabletedand may further be film coated with a protective coating which rapidlydissolves or disperses in gastric juices.

It should be noted that the above additives are not required for theamphetamine composition of the present technology to have sustainedrelease in vivo properties. The non-standard amino acid conjugates ofthe present technology are chemically stable to in vitro hydrolysis ofthe amide linkage to prevent tampering or removing the amphetamine priorto oral ingestion. Also, the controlled release of amphetamine throughoral administration of the non-standard amino acid conjugate of thepresent technology is an inherent property of the molecule, not relatedto the formulation. Put another way, the amphetamine prodrug of thepresent technology itself can control the release of amphetamine intothe digestive tract over an extended period of time resulting in animproved profile when compared to immediate release combinations andprevention of abuse without the addition of the above additives.Therefore, the prodrug of the present technology can be easilyformulated to different dosage forms. In one or more embodiments of thepresent technology, no further sustained release additives are requiredto achieve a blunted or reduced pharmacokinetic curve (e.g., reducedeuphoric effect) while achieving therapeutically effective amounts ofamphetamine release when taken orally.

The compounds and compositions of the presently described technology canbe formulated into and administered by a variety of dosage forms throughany oral routes of delivery. Once administered, the prodrugs willrelease amphetamine under digestive conditions. Anybiologically-acceptable dosage form known to persons of ordinary skillin the art, and combinations thereof, are contemplated. Examples ofpreferred dosage forms include, without limitation, chewable tablets,quick dissolve tablets, effervescent tablets, reconstitutable powders,elixirs, liquids, solutions, suspensions, emulsions, tablets,multi-layer tablets, bi-layer tablets, capsules, soft gelatin capsules,hard gelatin capsules, caplets, lozenges, chewable lozenges, beads,powders, granules, particles, microparticles, dispersible granules,cachets, oral films (e.g., fast dissolving thin strips), andcombinations thereof. Preferred dosage forms include capsule, solutionformulation, and fast dissolving oral film.

Formulations of the present technology suitable for oral administrationcan be presented as discrete units, such as capsules, caplets, tablets,or oral films. These oral formulations also can comprise a solution or asuspension in an aqueous liquid or a non-aqueous liquid. The formulationcan be an emulsion, such as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The oils can be administered by adding thepurified and sterilized liquids to a prepared enteral formula, which canthen be placed in the feeding tube of a patient who is unable toswallow.

If the capsule form is chosen, for example, excipients used in thecapsule formulation could be broken up into four separate groups: bulkagent/binder, disintegrant, lubricant and carrier. A preferred capsuleformulation comprises from about 50% to about 90% by weight a bulk agentsuch as various types of microcrystalline cellulose, from about 1% toabout 5% by weight of a disintegrant such as croscarmellose sodium, fromabout 0.5% to about 2.5% of a lubricant such as magnesium state or otherfatty acid salts. The carrier can be either hard gelatin capsules, andpreferably use the smaller size ones such as #3 or #4 hard gelatincapsules.

Soft gel or soft gelatin capsules may be prepared, for example, bydispersing the formulation of the present technology in an appropriatevehicle (vegetable oils are commonly used) to form a high viscositymixture. This mixture can then be encapsulated with a gelatin based filmusing technology and machinery known to those in the soft gel industry.The industrial units so formed are then dried to constant weight.

Chewable tablets, for example, may be prepared by mixing theformulations of the present technology with excipients designed to forma relatively soft, flavored, tablet dosage form that is intended to bechewed rather than swallowed. Conventional tablet machinery andprocedures, that is both direct compression and granulation, i.e., orslugging, before compression, can be utilized. Those individualsinvolved in pharmaceutical solid dosage form production are versed inthe processes and the machinery used as the chewable dosage form is avery common dosage form in the pharmaceutical industry.

Film-coated tablets, for example, may be prepared by coating tabletsusing techniques such as rotating pan coating methods or air suspensionmethods to deposit a contiguous film layer on a tablet.

Compressed tablets, for example, may be prepared by mixing theformulation of the present technology with excipients intended to addbinding qualities to disintegration qualities. The mixture can be eitherdirectly compressed or granulated then compressed using methods andmachinery known to those in the industry. The resultant compressedtablet dosage units are then packaged according to market need, i.e.,unit dose, rolls, bulk bottles, blister packs, etc.

One preferred formulation of the non-standard amino acids is a fastdissolving oral film or thin strip. Methods and other ingredients neededto make oral films or thin strips are known in the art. Potential filmforming agents include pullulan, hydroxypropylmethyl cellulose,hydroxypropyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol,sodium alginate, polyethylene glycol, xanthan gum, tragacanth gum, guargum, acacia gum, Arabic gum, polyacrylic acid, amylase, starch, dextrin,pectin, chitin, chitosin, levan, elsinan, collagen, gelatin, zein,gluten, soy protein isolate, whey protein isolate, casein, and mixturesthereof.

Also, saliva stimulating agents, plasticizing agents, cooling agents,surfactants, emulsifying agents, thickening agents, binding agentssweeteners, flavoring, coloring agents, preservatives, or taste maskingresins may be employed in the oral films or thin strips. Preferredagents include: pullulan, triethanol amine stearate, methyl cellulose,starch, triacetin, polysorbate 80, xanthan gum, maltitol, sorbitol andglycerol.

The presently described technology also contemplates the use ofbiologically-acceptable carriers which may be prepared from a wide rangeof materials. Without being limited thereto, such materials includediluents, binders and adhesives, lubricants, plasticizers,disintegrants, colorants, bulking substances, flavorings, sweeteners andmiscellaneous materials such as buffers and adsorbents in order toprepare a particular medicated composition.

Binders may be selected from a wide range of materials such ashydroxypropylmethylcellulose, ethylcellulose, or other suitablecellulose derivatives, povidone, acrylic and methacrylic acidco-polymers, pharmaceutical glaze, gums, milk derivatives, such as whey,starches, and derivatives, as well as other conventional binders knownto persons skilled in the art. Exemplary non-limiting solvents arewater, ethanol, isopropyl alcohol, methylene chloride or mixtures andcombinations thereof. Exemplary non-limiting bulking substances includesugar, lactose, gelatin, starch, and silicon dioxide.

Preferred plasticizers may be selected from the group consisting ofdiethyl phthalate, diethyl sebacate, triethyl citrate, cronotic acid,propylene glycol, butyl phthalate, dibutyl sebacate, castor oil andmixtures thereof, without limitation. As is evident, the plasticizersmay be hydrophobic as well as hydrophilic in nature. Water-insolublehydrophobic substances, such as diethyl phthalate, diethyl sebacate andcastor oil are used to delay the release of water-soluble vitamins, suchas vitamin B6 and vitamin C. In contrast, hydrophilic plasticizers areused when water-insoluble vitamins are employed which aid in dissolvingthe encapsulated film, making channels in the surface, which aid innutritional composition release.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations of the present technology can includeother suitable agents such as flavoring agents, preservatives andantioxidants. Such antioxidants would be food acceptable and couldinclude, for example, vitamin E, carotene, BHT or other antioxidantsknown to those of skill in the art.

Other compounds which may be included are, for example, medically inertingredients, e.g., solid and liquid diluent, such as lactose, dextrose,saccharose, cellulose, starch or calcium phosphate for tablets orcapsules, olive oil or ethyl oleate for soft capsules and water orvegetable oil for suspensions or emulsions; lubricating agents such assilica, talc, stearic acid, magnesium or calcium stearate and/orpolyethylene glycols; gelling agents such as colloidal clays; thickeningagents such as gum tragacanth or sodium alginate, binding agents such asstarches, arabic gums, gelatin, methylcellulose, carboxymethylcelluloseor polyvinylpyrrolidone; disintegrating agents such as starch, alginicacid, alginates or sodium starch glycolate; effervescing mixtures;dyestuff; sweeteners; wetting agents such as lecithin, polysorbates orlaurylsulphates; and other therapeutically acceptable accessoryingredients, such as humectants, preservatives, buffers andantioxidants, which are known additives for such formulations.

For oral administration, fine powders or granules containing diluting,dispersing and/or surface-active agents may be presented in a draught,in water or a syrup, in capsules or sachets in the dry state, in anon-aqueous suspension wherein suspending agents may be included, or ina suspension in water or a syrup. Where desirable or necessary,flavoring, preserving, suspending, thickening or emulsifying agents canbe included.

Liquid dispersions for oral administration may be syrups, emulsions orsuspensions. The syrups may contain as carrier, for example, saccharoseor saccharose with glycerol and/or mannitol and/or sorbitol. Thesuspensions and the emulsions may contain a carrier, for example anatural gum, agar, sodium alginate, pectin, methylcellulose,carboxymethylcellulose or polyvinyl alcohol.

The dose range for adult human beings will depend on a number of factorsincluding the age, weight and condition of the patient. Suitable oraldosages of the prodrugs of the presently described technology can be theequivalents of those typically found in amphetamine treatments. Typicaldosages for amphetamine salts can range from about 1 mg to about 100 mg,although higher dosages may be approved at later dates. Using themolecular weight of the prodrug of the present technology, the releasepercentage (% release) of amphetamine from the prodrug and desireddosage forms of the required amphetamine, the following equation can begenerated:

grams of a prodrug needed=(dosage/molecular weight of amphetamine)(%release)(molecular weight of the prodrug)

Tablets, capsules, oral films, and other forms of presentation providedin discrete units conveniently contain a daily dose, or an appropriatefraction thereof, of one or more of the compounds of the invention. Forexample, units may contain from about 1 mg to about 500 mg,alternatively from about 5 mg to about 250 mg, alternatively from about10 mg to about 100 mg of one or more of the compounds of the presentlydescribed technology.

It is also possible for the dosage form of the present technology tocombine any forms of release known to persons of ordinary skill in theart. These conventional release forms include immediate release,extended release, pulse release, variable release, controlled release,timed release, sustained release, delayed release, long acting, andcombinations thereof. The ability to obtain immediate release, extendedrelease, pulse release, variable release, controlled release, timedrelease, sustained release, delayed release, long acting characteristicsand combinations thereof is known in the art.

Compositions of the present technology may be administered in a partial,i.e., fractional dose, one or more times during a 24 hour period, asingle dose during a 24 hour period of time, a double dose during a 24hour period of time, or more than a double dose during a 24 hour periodof time. Fractional, double or other multiple doses may be takensimultaneously or at different times during the 24 hour period. Thedoses may be uneven doses with regard to one another or with regard tothe individual components at different administration times.

Likewise, the compositions of the present technology may be provided ina blister pack or other such pharmaceutical package. Further, thecompositions of the present technology may further include or beaccompanied by indicia allowing individuals to identify the compositionsas products for a prescribed treatment. The indicia may additionallyinclude an indication of the above specified time periods foradministering the compositions. For example, the indicia may be timeindicia indicating a specific or general time of day for administrationof the composition, or the indicia may be a day indicia indicating a dayof the week for administration of the composition. The blister pack orother combination package may also include a second pharmaceuticalproduct.

It will be appreciated that the pharmacological activity of thecompositions of the present technology can be demonstrated usingstandard pharmacological models that are known in the art. Furthermore,it will be appreciated that the compositions of the present technologycan be incorporated or encapsulated in a suitable polymer matrix ormembrane for site-specific delivery, or can be functionalized withspecific targeting agents capable of effecting site specific delivery.These techniques, as well as other drug delivery techniques, are wellknown in the art.

In one or more embodiments of the present technology, the solubility anddissolution rate of the composition can be substantially changed underdifferent physiological conditions encountered, for example, in theintestine, at mucosal surfaces, or in the bloodstream. In one or moreembodiments of the present technology, the solubility and dissolutionrate of the composition can substantially decrease the bioavailabilityof the amphetamine, particularly at doses above those intended fortherapy. In one embodiment of the present technology, the decrease inbioavailability occurs upon intranasal administration. In anotherembodiment, the decrease in bioavailability occurs upon intravenousadministration.

For each of the described embodiments of the present technology, one ormore of the following characteristics can be realized: Thecardiovascular toxicity of the amphetamine prodrug is substantiallylower than that of the unconjugated amphetamine and amphetamineconjugated with a standard amino acid. The covalently bound non-standardamino acid moiety reduces or eliminates the possibility of behavioraldeterioration or the rebound effect. The covalently bound non-standardamino acid moiety reduces or eliminates the possibility of abuse byintranasal administration. The covalently bound non-standard amino acidmoiety reduces the possibility of abuse by injection.

The presently described technology further provides methods for alteringand/or delivering amphetamines in a manner that can decrease theirpotential for abuse. Methods of the present technology provide variousways to regulate pharmaceutical dosage through conjugating amphetaminewith non-standard amino acids.

One embodiment provides a method for preventing behavioral deteriorationor the rebound effect by administering to a patient in need anamphetamine prodrug composition of the present technology, whichcomprises at least one non-standard amino acid conjugate of amphetamine.

Another embodiment provides a method for safely delivering amphetaminecomprising providing a therapeutically effective amount of at least onenon-standard amino acid conjugate of amphetamine wherein thenon-standard amino acid moiety can reduce the rate of absorption ofamphetamine as compared to delivering the unconjugated amphetamine oramphetamine conjugated with a standard amino acid.

Another embodiment provides a method for reducing amphetaminecardiovascular toxicity comprising providing a patient with at least onenon-standard amino acid conjugate of amphetamine, wherein the amino acidmoiety can decrease the rate of release of amphetamine within the firsta few hours of administration.

Another embodiment provides a method for reducing amphetaminecardiovascular toxicity comprising providing a patient with at least onenon-standard amino acid conjugate of amphetamine, wherein the amino acidmoiety can provide a serum release curve which does not increase abovethe amphetamine's cardiovascular toxicity level.

Another embodiment provides a method for reducing bioavailability ofamphetamine or for preventing a toxic release profile of amphetamine ina patient, comprising providing at least one non-standard amino acidconjugate of amphetamine, wherein the conjugated amphetamine canmaintain a steady-state serum release curve which provides atherapeutically effective bioavailability but prevents spiking orincreased blood serum concentrations compared to amphetamine conjugatedwith a standard amino acid.

Another embodiment provides a method for preventing a C_(max) orequivalent C_(max) spike for amphetamine while still providing atherapeutically effective bioavailability curve comprising the step ofadministering to a patient at least one non-standard amino acidconjugate of amphetamine.

Another embodiment of the present technology is a method for reducing orpreventing abuse of amphetamine comprising providing, administering,consuming, or prescribing a composition to a patient in need thereof,wherein said composition comprises at least one non-standard amino acidconjugate of amphetamine such that the pharmacological activity ofamphetamine is decreased when the composition is used in a mannerinconsistent with the manufacturer's instructions.

Another embodiment of the present technology is a method of preventingbehavioral deterioration or the rebound effect of amphetamine orstimulant treatment comprising providing, administering, consuming, orprescribing an amphetamine composition of the presently describedtechnology to a patient in need thereof, wherein said compositioncomprises at least one non-standard amino acid conjugate of amphetaminethat can decrease the potential of behavioral deterioration or therebound effect from amphetamine or stimulant treatment.

Another embodiment of the present technology is a method for reducing orpreventing the euphoric effect of amphetamine comprising providing,administering, or prescribing to a human in need thereof, or consuming acomposition comprising at least one non-standard amino acid conjugate ofamphetamine that can decrease the pharmacological activity ofamphetamine when the composition is used in a manner inconsistent withthe manufacturer's instructions.

Another embodiment of the present technology is any of the precedingmethods wherein the amphetamine composition used is adapted for oraladministration, and wherein the amphetamine prodrug is resistant torelease amphetamine from the non-standard amino acid moiety when thecomposition is administered parenterally, such as intranasally orintravenously. Preferably, amphetamine may be released from thenon-standard amino acid moiety in the presence of the intestinal tract.Optionally, the amphetamine composition used may be in the form of atablet, capsule, oral film, oral solution, oral suspension, or otheroral dosage form discussed herein.

For one or more of the recited methods, the composition of the presenttechnology used may yield a therapeutic effect without substantialeuphoria. Preferably, the amphetamine composition of the presenttechnology can provide a therapeutically bioequivalent AUC when comparedto other controlled release amphetamine compositions but does notprovide a C_(max) which results in euphoria or an equivalent C_(max).

For one or more of the recited methods of the present technology, thefollowing properties may be achieved through conjugating amphetamine toa non-standard amino acid. In one embodiment, the cardiovasculartoxicity or stress of the non-standard amino acid conjugate ofamphetamine of the present technology may be lower than that of theamphetamine when the amphetamine is delivered in its unconjugated state,as a compound conjugated to a standard amino acid, or as a salt thereof.In another embodiment, the possibility of behavioral deterioration isreduced or eliminated. In another embodiment, the possibility of abuseby intranasal administration is reduced or eliminated. In anotherembodiment, the possibility of abuse by intravenous administration isreduced or eliminated.

Another embodiment of the present technology provides methods oftreating various diseases or conditions requiring the stimulation of thecentral nervous system (CNS) comprising administering compounds orcompositions of the present technology which, optionally, furthercomprise commonly prescribed active agents for the respective illness ordisease. For instance, one embodiment of the invention comprises amethod of treating attention deficit hyperactivity disorder (ADHD)comprising administering to a patient at least one non-standard aminoacid conjugate of amphetamine. Another embodiment provides a method oftreating attention deficit disorder (ADD) comprising administering to apatient compounds or compositions of the invention.

Another embodiment of the invention provides a method of treatingnarcolepsy comprising administering to a patient compounds orcompositions of the presently described technology.

The presently described technology and its advantages will be betterunderstood by reference to the following examples. These examples areprovided to describe specific embodiments of the present technology. Byproviding these specific examples, the applicants do not limit the scopeand spirit of the present technology. It will be understood by thoseskilled in the art that the full scope of the presently describedtechnology encompasses the subject matter defined by the claimsappending this specification, and any alterations, modifications, orequivalents of those claims.

Example 1 Comparative Study of Pharmacokinetic Parameters of ReleasedD-Amphetamine Following Administration of a Non-Standard Amino AcidConjugate (hArg-Amp) and a Standard Amino Acid Conjugate (Vyvanse™,Lys-Amp)

The Pharmacokinetic Parameters of D-Amphetamine Following OralAdministration of a non-standard amino acid conjugate of the presenttechnology and a standard amino acid conjugate, Vyvanse™ (Lys-Amp),commercially available from Shire, Incorporated of Wayne, Pa. arestudied in this example. The non-standard amino acid conjugate used inthis example is the hydrochloride salt of hArg-Amp. The results arerecorded in the table below:

TABLE 1 Non-standard amino acid Parameter % amp¹ Vyvanse ™ % total Amp²AUC_(0-8 h) 94% 100% AUC_(0-4 h) 77% 100% AUC_(inf) 95% 100% C_(max) 76%100% T_(max) 400%  100% ¹Percent amphetamine released relative toVyvanse ™ (at an equimolar concentration of amphetamine contained in thenon-standard amino acid prodrug compared to the total amphetaminecontained in Vyvanse ™) ²Percent amphetamine relative to 50 mg Vyvanse ™dose

The study shows that the C_(max) of a prodrug of the preset technologyis significantly lower than that of Vyvanse™, a standard amino acidconjugate of d-amphetamine, which can lead to lower cardiovasculareffects (blood pressure, heart rate). Quick release (higher C_(max)) ofamphetamine has already demonstrated significant increases in bloodpressure and heart rate. In certain patient populations, thesecardiovascular side effects can be dose limiting or can cause thetermination of stimulant therapy.

The pharmacokinetic parameters of d-amphetamine following parentaladministration of hArg-Amp and d-amphetamine are also studied. The studyshows that little release of amphetamine (<50%) happens when hArg-Amp istaken through parental routes (intranasal, intravenous) due todifferences in enzymes encountered in gut versus other routes. WhenAdderall X® or other controlled release formulations of amphetamine areinjected or snorted, the pharmacokinetic parameters of the amphetamineare significantly altered and an individual can use these changes toproduce euphoria.

Example 2 Preparation of Boc-Orn(Boc)-Amp

Boc-Orn(Boc)-OH (1.5 g, 4.518 mmol) was dissolved in DMF (15 ml). EDCI(1.299 g, 6.777 mmol), NHS (0.572 g, 4.969 mmol), d-amphetamine (0.732g, 5.422 mmol) and DIEA (0.87 ml, 4.969 mmol) were then addedsequentially. The clear reaction mixture was stirred at room temperaturefor 16 hours (hrs). The reaction mixture was quenched with pH 3 water(40 ml), and the product was extracted with EtOAc (3×70 ml). Thecombined extracts were washed with pH 3 water, saturated NaHCO₃ followedby water. The EtOAc layer was dried over anhydrous Na₂SO₄. Solvent wasremoved to obtain 1.82 g of protected amide as a white solid.

The white solid was analyzed by ¹H NMR (CDCl₃) δ. The results show1.1-1.2 (m, 3H, Amp α-CH₃), 1.3-1.5 (m, 18H, Boc CH₃), 1.6-1.8 (m, 4H,Orn δ CH₂), 2.75 (m, 2H, Amp β CH₂), 3.05-3.1 (m, 2H, Orn δ CH₂), 3.2(m, 1H, Amp a CH), 4.1 (m, 1H, Orn α CH), 7.1-7.4 (m, 5H, Amp Ar—H).These NMR shifts are consistant with the structure of Orn-Amp.

Example 3 Preparation Of Orn-Amp

Boc-Orn(Boc)-Amp (1.35 g, 3 mmol) was dissolved in EtOAc (200 ml) and tothe slightly cloudy solution was added MsOH (0.43 ml, 6.6 mmol) dropwise. The reaction mixture became a clear solution which was stirred atroom temperature for approximately 20 hrs. Solvent was removed and theresidue was triturated in hexanes. Off-white solid product was formedwhich was filtered under vacuum and washed with hexanes. The solid wasdried in vacuum oven for 20 hrs to obtain 0.88 g of Orn-Amp.2MsOH(1-ornithine-d-amphetamine dimesylate).

The product obtained was tested by ¹H NMR (DMSO-d₆) δ. The result shows1.1 (m, 3H, Amp α-CH₃), 1.4-1.6 (m, 4H, Orn β, γ CH₂), 2.35 (s, 6H,CH₃SO₃H CH₃), 2.6-2.8 (m, 4H, Amp β and Orn δ), 3.75 (m, 1H, Amp α),4.05 (m, 1H, Orn α), 7.1-7.3 (m, 5H, Amp Ar—H), 7.6-8.5 (br peaks, amideand amine); ¹³C NMR (DMSO-d₆) δ 18.45 (Orn γ), 21.49 (Orn β), 27.30 (Ampβ), 37.38 (Amp CH₃), 37.77 (Amp α), 41.20 (Orn δ), 51.54 (Orn α), 125.29(p-Ar), 127.27 (r-Ar), 129.17 (o-Ar), 137 (Ar), 166.58 (C═O); M+1=250.7.These results are consistent with the proposed structure.

Example 4 Preparation of Boc-hArg(NO₂)-Amp

Boc-hArg(NO₂)—OH (2.667 g, 8 mmol) was dissolved in DMF (25 ml). EDCI(2.30 g, 12 mmol), NHS (1.012 g, 8.8 mmol), d-amphetamine (1.269 g, 9.6mmol) and DIEA (1.138 g, 8.8 mmol) were then added sequentially. Theclear reaction mixture was stirred at room temperature for 16 hrs. Thereaction mixture was quenched with pH 3 water (150 ml), and the productwas extracted with EtOAc (3×50 ml). The combined extracts were washedwith pH 3 water followed by saturated NaCl. The EtOAc layer was driedover anhydrous MgSO₄. The product was recrystallized from EtOAc-Hexanetwo times to give 2.36 g of desired protected product.

The product was analyzed using ¹H NMR (DMSO-d₆) δ. The result shows0.9-1.1 (m, 3H, Amp CH₃), 1.1-1.2 (m, 2H, hArg γ CH₂), 1.2-1.5 (m, 13H,Boc CH₃, hArg β,δ CH₂), 2.55-2.75 (m, 2H, Amp β CH₂), 3.1 (m, 2H, hArgCH₂), 3.75 (m, 1H, Amp α CH), 3.95 (m, 1H, hArg α CH), 6.65 (t, 1H, hArgguanidino NH), 7.1-7.3 (m, 5H, Amp Ar—H), 7.6-8.2 (br m, 2H, hArgguanidine NH and amide NH), 8.5 (br s, 1H, hArg NH—NO₂). These resultswould be considered consistent with the proposed structure.

Example 5 Preparation of hArg-Amp-2HCl (L-Homoarginine-D-AmphetamineDihydrochloride)

Boc-hArg(NO₂)-Amp (1.5 g) was dissolved in HPLC grade MeOH (120 ml) andto the clear solution was added the Pd—C catalyst (10%, Aldrich). Asmall stir bar was placed in the flask and the reaction mixture wasstirred under a slow stream of hydrogen overnight after incorporatingthe 5-6N HCl in 2-propanol solution (1.5 ml). After the overnightreaction, the solution was filtered and the solvent evaporated. Thewhite crystalline product was dried under vacuum to give 1.61 g of theBoc-hArg-Amp intermediate product.

The product (1.6 g) was dissolved in 80 ml of HPLC grade MeOH, and 5-6NHCl in 2-propanol (3.2 mL) was added to the solution. The reactionmixture was stirred overnight, solvent removed and re-dissolved inminimum amount of MeOH. The final product was crashed out with MTBE, anddried under vacuum at 30° C. for about 20 hours to yield 1.12 g of awhite powder.

The white powder was analyzed using ¹H NMR (DMSO-d₆) δ. The result shows0.9-1.1 (m, 3H, Amp CH₃), 1.1-1.2 (m, 2H, hArg γ CH₂), 1.35 (m, 2H, hArgβ CH₂), 1.55 (m, 2H, hArg δ CH₂), 2.75 (d, 2H, Amp β CH₂), 3.0 (m, 2H,hArg ε CH₂), 3.75 (m, 1H, Amp α CH), 4.05 (m, 1H, hArg α CH), 7.1-7.2(m, 5H, Amp Ar—H), 7.2-7.8 (br m, 3H, amide NH, HCl), 8.0 (t, 1H, hArgguanidino NH), 8.2 (br s, 2H, amide or guanidino NH₂), 8.75 (d, 1H,amide NH); ¹³C NMR (DMSO-d₆) δ 21.08 (Amp CH₃), 21.36 (hArg γ), 28.23(hArg δ), 32.28 (hArg β), 40.18 (Amp β), 42.19 (hArg ε), 46.88 (Amp α),52.23 (hArg a), 126.54 (p-Ar), 128.52 (m-Ar), 129.60 (o-Ar), 139.34(Ar), 157.61 (C═O), 167.95 (guanidino C); M+1=306. These results wouldbe considered to be consistant with the proposed structure.

Example 6 Preparation of Cit-Amp-HCl (L-Citrulline-D-AmphetamineHydrochloride)

Boc-Cit-OH (0.50₀ g, 1.82 mmol) was dissolved in anhydrous THF. To thissolution was added NHS (0.209 g, 1.82 mmol) followed by DCC (0.376 g,1.82 mmol). Resulting slurry was stirred at ambient temperatureovernight. In a separate flask, d-amphetamine sulfate (0.306 g, 0.83mmol) was suspended in THF (10 ml) and NMM (0.34 ml, 3.64 mmol) wasadded. The activated ester was filtered directly into the amphetaminesuspension and the resulting suspension was stirred overnight. Thereaction was quenched with 5% NaHCO₃ and IPAC for 45 min. Organicsolvent was then removed. The aqueous layer was then extracted 3 timeswith IPAC and the combined organics were washed with 5% acetic acid, 5%NaHCO₃ and 5% NaCl. The organic layer was then dried over NaSO₄ andsolvent was removed. Crude product was re-crystallized usingIPAC/heptane to yield 200 mg of a white solid.

10 ml of 4N HCl in dioxane were added to the 200 mg (0.200 g)Boc-Cit-Amp. The mixture was stirred at room temperature for 6 hours andsolvent was removed.

Example 7 Comparative Biological Study of Lys-Amp and hArg-Amp

Male Sprague-Dawley rats were fasted overnight and dosed by oral gavagewith either 1-homoarginine-d-amphetamine (hArg-Amp) or1-lysine-d-amphetamine (Vyvanse™, Lys-Amp). Water was provided adlibitum. Doses were calculated at an equivalent 1.5 mg/kg freebaseequivalent of d-amphetamine. Plasma concentrations of d-amphetamine weremeasured using ELISA (Neogen Corp. Lexington, Ky.).

Mean plasma concentration curves (n=5) of d-amphetamine released byl-homoarginine-d-amphetamine or 1-lysine-d-amphetamine are shown inFIG. 1. Pharmacokinetic(PK) parameters of this study are listed in Table2.

TABLE 2 PHARMACOKINETIC PROPERTIES OF HARG-AMP AND LYS-AMP Vehicle % AUCTmax Cmax % Tmax % Cmax Lys-Amp 100% 3 h 44 ng/ml 100% 100% hArg-Amp 99%4 h 44 ng/ml 133% 100%

This pharmacokinetic (PK) study clearly demonstrates a shift in theT_(max) for the non-standard amino acid (hArg-Amp) compared to thestandard amino acid (Lys-Amp). This shift may be due to a reduction inthe rate of enzymatic hydrolysis of the amide bond of the non-standardamino acid attached to amphetamine vs. the standard amino acid attachedto amphetamine.

FIGS. 2-4 represent different ways to view the data reflected in FIG. 1and Table 2. As further discussed below, these figures highlight thedifferences of hArg-Amp over Lys-Amp during the first several hours.

FIG. 2 demonstrates the relative blood levels of d-amphetamine releasedfrom both Lys-Amp and hArg-Amp. The graph shows that equivalent bloodlevels do not occur until later time points and that blood levels do notappear to spike or have a more significant C_(max) than Lys-Amp. Theamount of d-amphetamine released from hArg-Amp is gradual and maintainsa more steady concentration over the duration of the study than didLys-Amp. In contrast, Lys-Amp blood levels of released d-amphetamine“spiked” at 3 hours and cleared more quickly than the blood levelsobtained from hArg-Amp.

FIGS. 3 and 4 show the difference in blood levels obtained from thestudy described in FIG. 2. As is shown, the initial blood levels forboth conjugates (Lys-Amp and hArg-Amp) are very different, with hArg-Ampreleasing amphetamine at a more gradual rate. These differences in bloodlevels become less during the more critical duration of action forstimulant treatments and more importantly, the differences are greateragain at later time points suggesting that hArg-Amp maintains a moreconsistent dose of amphetamine when compared to Lys-Amp. The longerduration of release for hArg-Amp would suggest a much lower opportunityfor behavioral deterioration to occur.

Other oral studies have been conducted in a similar fashion and aresummarized in Table 3 below. The average PK results for four (4) oralstudies (n=20 per vehicle) are recorded in FIG. 5:

TABLE 3 AVERAGE RESULTS OF 4 ORAL STUDIES (N = 20 PER COMPOUND) Vehicle% AUC Tmax % Tmax % Cmax % AUC 0-4 h Lys-Amp 100% 1 h 100% 100% 100%hArg-Amp 94% 4 h 400% 76% 77%

Example 8 Biological Study of Harg-Amp and Orn-Amp

To compare the amount of release of d-amphetamine among variousnon-standard amino acids, 1-ornithine-d-amphetamine (Orn-Amp) was dosedin replace of Lys-Amp in Example 7 in another oral pharmacokineticstudy. Mean plasma concentration curves (n=5) of d-amphetamine releasedby hArg-Amp or Orn-Amp are shown in FIG. 6. Pharmacokinetic parametersof this study are listed in Table 4.

TABLE 4 PHARMACOKINETIC PROPERTIES OF HARG-AMP AND ORN-AMP Vehicle % AUCTmax Cmax % Tmax % Cmax hArg-Amp 100% 4 h 32 ng/ml 100% 100% Orn-Amp 78%1 h 27 ng/ml 25% 84%

Example 9 Comparative Biological Study of Lys-Amp, Harg-Amp, Orn-Amp andCit-Amp

To compare the amount of release of d-amphetamine among variousnon-standard amino acids, 1-ornithine-d-amphetamine (Orn-Amp), hArg-Ampand l-citrulline-d-amphetamine (Cit-Amp) were dosed with Lys-Amp inanother oral pharmacokinetic study. Mean plasma concentration curves(n=5) of d-amphetamine released by hArg-Amp, Orn-Amp and Cit-Amp areshown in FIG. 7. Pharmacokinetic parameters of this study are listed inTable 5.

Direct comparison of 3 non-standard amino acid conjugates of amphetamine(Cit, Orn and hArg) demonstrate the significant ability to shift orchange the pharmacokinetic properties versus the standard amino acids.All non-standard amino acids studied released amphetamine in an amountgreater than 50%. Ornithine and homoarginine both showed C_(max) levelsfar below that of lysine and both homoarginine and citrullinesignificantly shifted the T_(max) compared to Lys-Amp. These changes tothe pharmacokinetic properties of amphetamine when conjugated tonon-standard amino acids represent clinically significant changes notdescribed or demonstrated by Lys-Amp nor described or demonstrated byother standard amino acids.

TABLE 5 ORAL PROPERTIES OF LYS-AMP, HARG-AMP, ORN-AMP AND CIT-AMPVehicle % AUC Tmax Cmax % Tmax % Cmax Lys-Amp 100%  1 h 59 ng/ml 100%100% hArg-Amp 68%  2 h 27 ng/ml 200% 46% Orn-Amp 52%  1 h 32 ng/ml 100%54% Cit-Amp 95% 15 m 129 ng/ml  25% 219%

Example 10 Intranasal Study of Amp, Harg-Amp, Orn-Amp

Male Sprague-Dawley rats were fasted overnight and dosed by intranasaladministration with either hArg-Amp, Orn-Amp or d-amphetamine. Doseswere calculated at an equivalent 1.5 mg/kg freebase equivalent ofd-amphetamine. Plasma concentrations of d-amphetamine were measuredusing ELISA. Mean plasma concentration curves (n=5) of d-amphetaminereleased by hArg-Amp or Orn-Amp are shown in FIG. 8. Pharmacokineticparameters of this study are listed in Table 6. No significant release(<25%) was observed in either hArg-Amp or Orn-Amp.

TABLE 6 INTRANASAL PROPERTIES OF D-AMP, HARG-AMP AND ORN-AMP Vehicle %AUC Tmax Cmax % Tmax % Cmax d-amp 100% 15 m 53 ng/ml 100% 100% hArg-Amp23%  2 h  9 ng/ml 1600% 17% Orn-Amp 14%  2 h 10 ng/ml 1600% 19%

Example 11 Intravenous Study of Amp, Harg-Amp, Orn-Amp

Male Sprague-Dawley rats were dosed by intravenous administrationthrough the tail vein with hArg-Amp, Orn-Amp or d-amphetamine. Doseswere calculated at an equivalent 1.5 mg/kg freebase equivalent ofd-amphetamine. Plasma concentrations of d-amphetamine were measuredusing ELISA. Mean plasma concentration curves (n=5) of d-amphetaminereleased by hArg-Amp or Orn-Amp are shown in FIG. 9. Pharmacokineticparameters of this study are listed in Table 7. No significant release(<35%) was observed in either hArg-Amp or Orn-Amp. The initial spike ind-amphetamine released from hArg-Amp cleared quickly while as in theintranasal study, Orn-Amp had a slight increase at the 2 hour point.

TABLE 7 INTRAVENOUS PROPERTIES OF D-AMP, HARG-AMP AND ORN-AMP Vehicle %AUC Tmax Cmax % Tmax % Cmax d-amp 100% 15 m 396 ng/ml 100% 100% hArg-Amp41% 15 m 135 ng/ml 100% 34% Orn-Amp 10% 15 m  26 ng/ml 100% 7%

Results of the studies in Examples 7-11 clearly show an unexpectedchange in the oral pharmacokinetic properties by using non-standardamino acids over standard amino acids. By changing the non-standardamino acid attached to amphetamine, the conjugates are able to shiftT_(max) (earlier or later), modify curve shape, lower C_(max), and raiseC_(max). In addition, the shift in T_(max) for hArg-Amp may beclinically significant in that many of the cardiovascular side effectsand toxicity are related to T_(max) and C_(max). The results demonstratethat by using non-standard amino acids a shift in the T_(max), with alower C_(max) occurs without changing AUC significantly. In addition,the slope of uptake of hArg-Amp vs. Lys-Amp appears to be more gradualthus leading to a slower onset which could further alleviate sideeffects.

The amphetamine conjugate, hArg-Amp, of the present technologydemonstrates that by using non-standard amino acids, a shift in theT_(max) occurs while still retaining AUC and potential clinical effect.By using non-standard amino acids, we are able to demonstrate that bothhArg-Amp and Orn-Amp show little release via the IN and IV route yetstill maintain a similar AUC.

The presently described technology is now described in such full, clear,concise and exact terms as to enable any person skilled in the art towhich it pertains, to practice the same. It is to be understood that theforegoing describes preferred embodiments of the invention and thatmodifications may be made therein without departing from the spirit orscope of the invention as set forth in the appended claims.

1. A composition for treating a human or animal patient having adisorder or condition requiring the stimulation of the central nervoussystem of the patient, comprising at least one conjugate of amphetaminewith ornithine or homoarginine, a salt thereof, a derivative thereof, ora combination thereof.
 2. The composition of claim 1, wherein at leastone conjugate of amphetamine is l-ornithine-d-amphetamine.
 3. Thecomposition of claim 1, wherein at least one conjugate of amphetamine isl-homoarginine-d-amphetamine.
 4. The composition of claim 1, wherein thecomposition having a reduced or prevented pharmacological activity whenadministered by parenteral routes.
 5. The composition of claim 1,wherein the salt of the conjugate of amphetamine is a mesylate, ahydrochloride salt, a sulfate, an oxalate, a triflate, a citrate, amalate, a tartrate, a phosphate, a nitrate, a benzoate, or a mixturethereof.
 6. The composition of claim 1, wherein the composition is inthe form of a tablet, a capsule, a caplet, a troche, a lozenge, an oralpowder, a solution, a oral film, a thin strip, or a suspension.
 7. Thecomposition of claim 6, wherein the tablet, troche, or lozenge ischewable.
 8. The composition of claim 1, wherein at least one conjugateof amphetamine, the salt thereof, derivative thereof, or the combinationthereof is present in the amount of from about 1 mg to about 500 mg. 9.The composition of claim 1, wherein at least one conjugate ofamphetamine, the salt thereof, derivatives thereof, or the combinationthereof is present in the amount of from about 5 mg to about 250 mg. 10.The composition of claim 1, wherein at least one conjugate ofamphetamine, the salt thereof, derivatives thereof, or the combinationthereof is present in the amount of from about 10 mg to about 100 mg.11. The composition of claim 1, wherein at least one conjugate ofamphetamine, the salt thereof, the derivative thereof, or thecombination thereof is in an amount sufficient to provide atherapeutically bioequivalent AUC when compared to amphetamine alone,but does not provide a C_(max) spike.
 12. The composition of claim 1,wherein at least one conjugate of amphetamine, the salt thereof, thederivative thereof, or the combination thereof is in an amountsufficient to provide a therapeutically bioequivalent AUC when comparedto amphetamine alone, but does not provide an equivalent C_(max).
 13. Amethod for treating a patient having a disorder or condition requiringthe stimulation of the central nervous system of the patient, comprisingorally administering to the patient a pharmaceutically effective amountof at least one conjugate of amphetamine with ornithine or homoarginine,a salt thereof, a derivative thereof, or a combination thereof.
 14. Thecomposition of claim 13, wherein at least one conjugate of amphetamineis l-ornithine-d-amphetamine.
 15. The composition of claim 13, whereinat least one conjugate of amphetamine is l-homoarginine-d-amphetamine.16. The method of claim 13, wherein said step of orally administeringcomprises administering a tablet, a capsule, a caplet, a troche, alozenge, an oral powder, an oral solution, an oral film, a thin strip,or an oral suspension.
 17. The method of claim 13, wherein the conjugateof amphetamine is administered in the form of a salt.
 18. The method of17, wherein the salt is a mesylate, a hydrochloride salt, a sulfate, anoxalate, a triflate, a citrate, a malate, a tartrate, a phosphate, anitrate, a benzoate, or a mixture thereof.
 19. The method of claim 13,comprising administering a dosage form containing from about 1 mg toabout 500 mg of the at least one conjugate of amphetamine, the saltthereof, the derivative thereof, or the combination thereof.
 20. Themethod of claim 13, comprising administering a dosage form containingfrom about 5 mg to about 250 mg of the at least one conjugate ofamphetamine, the salt thereof, or the combination thereof.
 21. Themethod of claim 13, comprising administering a dosage form containingfrom about 10 mg to about 100 mg of the at least one conjugate ofamphetamine, the salt thereof, or the combination thereof.
 22. Themethod of claim 13, wherein at least one conjugate of amphetamine, thesalt thereof, or the combination thereof is in an amount sufficient toprovide a therapeutically bioequivalent AUC when compared to amphetaminealone, but does not provide a C_(max) spike.
 23. The method of claim 13,wherein the at least one conjugate of amphetamine, the salt thereof, orthe combination thereof is in an amount sufficient to provide atherapeutically bioequivalent AUC when compared to amphetamine alone,but does not provide an equivalent C_(max).
 24. The method of claim 13,wherein the disorder or condition is attention deficit hyperactivitydisorder, attention deficit disorder, obesity, narcolepsy, appetitesuppression, depression, anxiety, wakefulness, or a combination thereof.25. The method of claim 24, wherein the disorder or condition isattention deficit hyperactivity disorder.
 26. The method of claim 24,wherein the disorder or condition is attention deficit disorder.
 27. Themethod of claim 24, wherein the disorder or condition is obesity. 28.The method of claim 24, wherein the disorder or condition is appetitesuppression.
 29. The method of claim 24, wherein the disorder orcondition is depression.
 30. The method of claim 24, wherein thedisorder or condition is narcolepsy.